Retrotrapezoid nucleus and central chemoreception

梯形后核和中枢化学感受

• 批准号: 8466355
• 负责人: Patrice G. Guyenet
• 金额: $ 40.22万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466355
• 关键词: Acute; Address; Adult; Affect; Anesthesia procedures; Animals; Apnea; Arousal; Biochemical; Birth; Blood Pressure; Blood gas; Brain Part; Brain Stem; Breathing; Carbon Dioxide; Carotid Body; Cell Nucleus; Cells; Chemicals; Chemoreceptors; Clinical; Code; Collection; Conscious; Defect; Development; Dorsal; Fatigue; Frequencies; Genes; Grant; Halorhodopsins; Health; Hereditary Disease; Homeostasis; Human; Hypercapnic respiratory failure; Hypertension; Intervention; Label; Lentivirus Vector; Life; Mammals; Membrane; Metabolic; Methods; Mus; Muscle; Mutate; Neurons; Neurotransmitters; Obstructive Sleep Apnea; Opiates; Output; Oxygen; Pain; Pattern; Phenotype; Play; Pontine structure; Population; Property; Rattus; Regulation; Research; Rodent; Role; Serotonin; Sleep; Sleep Apnea Syndromes; Subfamily lentivirinae; Sudden infant death syndrome; System; Testing; Therapeutic; Time; Transfection; Ventilatory Depression; Work; base; clinically relevant; congenital central hypoventilation syndrome; fascinate; in vivo; mouse model; neuromechanism; neuron loss; neurophysiology; neuroregulation; noradrenergic; novel; optogenetics; prevent; public health relevance; research study; respiratory; response; selective expression; tissue oxygenation; tool; vigilance

DESCRIPTION (provided by applicant): The central neural mechanisms that maintain breathing and achieve blood gas homeostasis during sleep have considerable clinical relevance for congenital central hypoventilation syndrome (CCHS), central and obstructive sleep apnea (OSA), sudden infant death syndrome (SIDS) and the treatment of pain with opiates. Under the auspices of this grant, we have identified and extensively characterized a population of lower brainstem neurons (ccRTN neurons) that could be playing a pivotal role in the CO2-mediatedregulation of breathing. The activity of these neurons is exquisitely sensitive to CO2 in vivo due to the fact that they respond directly to changes in the surrounding pH and receive powerful input from the oxygen and CO2- sensing carotid bodies. Furthermore, we have shown that the ccRTN neurons provide a strong excitatory drive to the respiratory pattern generator (RPG) and that their absence eliminates RPG activity under anesthesia regardless of the level of CO2. Recent findings of major significance to CCHS suggest that the ccRTN neurons may be even more important for CO2 homeostasis in conscious mammals than anticipated. Without input from these neurons, breathing may not be possible during sleep. In 2006, we demonstrated that, in rodents, the ccRTN neurons express Phox2b, the defining mutated gene in CCHS identified in 2003. The cardinal signs of CCHS are day time hypoventilation, total sleep apnea and loss of breathing stimulation by CO2. In 2008/9, geneticists found that the ccRTN neurons are selectively absent at birth in a mouse model of CCHS. In other words, the input-output properties of the ccRTN neurons, as we understand them currently, seem precisely appropriate for these cells to contribute to CO2 homeostasis via breathing. The genetic disease, CCHS, suggests that these neurons are critical in this regard, especially during sleep. These possibilities are fascinating and deserve to be thoroughly tested, not merely for their importance in CCHS but for their control of breathing during sleep in normal animals. Accordingly, the main objectives of this renewal application are: a) to assess the importance of the ccRTN neurons for involuntary breathing during various states of vigilance, b) to determine how the ccRTN neurons control breathing, specifically which respiratory neurons they target, and c) to further examine how the activity of the ccRTN neurons is regulated with special focus on their control by serotonin, another major neurotransmitter involved in breathing. The results from the proposed experiments will help to determine whether selective stimulation of these neurons could offer a therapeutic opportunity when hypoventilation is detrimental to health, e.g. OSA. To address these issues we will continue using the large repertoire of neurophysiological and neuroanatomical methods that we have developed in prior years and we will make heavy use of a new lentiviral vector approach to manipulate ccRTN neurons selectively in vivo, a method that has allowed us to unleash the power of optogenetics for the study of cardiorespiratory control.

描述（由申请人提供）：睡眠期间维持呼吸和实现血气稳态的中枢神经机制与先天性中枢性低通气综合征（CCHS）、中枢性和阻塞性睡眠呼吸暂停（OSA）、婴儿猝死综合征（SIDS）和阿片类药物治疗疼痛具有相当大的临床相关性。在这项资助的支持下，我们已经确定并广泛表征了可能在二氧化碳介导的呼吸调节中起关键作用的下脑干神经元（ccRTN神经元）群体。这些神经元的活动在体内对二氧化碳非常敏感，因为它们直接响应周围pH值的变化，并接受来自氧气和二氧化碳感知颈动脉体的强大输入。此外，我们已经证明ccRTN神经元为呼吸模式发生器（RPG）提供了强烈的兴奋驱动，并且无论二氧化碳水平如何，它们的缺失都会消除麻醉下的RPG活动。最近对CCHS有重大意义的发现表明，ccRTN神经元对有意识的哺乳动物的二氧化碳稳态可能比预期的更重要。没有这些神经元的输入，睡眠时可能无法呼吸。2006年，我们证明，在啮齿类动物中，ccRTN神经元表达Phox2b，这是2003年发现的CCHS的决定性突变基因。CCHS的主要症状是白天通气不足，完全睡眠呼吸暂停和二氧化碳呼吸刺激丧失。在2008/ 2009年，遗传学家发现ccRTN神经元在CCHS小鼠模型出生时选择性缺失。换句话说，ccRTN神经元的输入输出特性，正如我们目前所理解的，似乎正好适合这些细胞通过呼吸来促进二氧化碳的稳态。这种名为CCHS的遗传病表明，这些神经元在这方面至关重要，尤其是在睡眠时。这些可能性令人着迷，值得进行彻底的测试，不仅因为它们在CCHS中的重要性，而且因为它们在正常动物睡眠时控制呼吸。因此，本更新应用的主要目的是：a)评估ccRTN神经元在各种警觉状态下对不自主呼吸的重要性，b)确定ccRTN神经元如何控制呼吸，特别是它们针对哪些呼吸神经元，以及c)进一步研究ccRTN神经元的活动是如何被调节的，特别关注血清素（另一种参与呼吸的主要神经递质）的控制。实验结果将有助于确定当低通气对健康有害时，如阻塞性呼吸暂停，选择性刺激这些神经元是否可以提供治疗机会。为了解决这些问题，我们将继续使用我们在前几年开发的大量神经生理学和神经解剖学方法，我们将大量使用一种新的慢病毒载体方法来选择性地在体内操纵ccRTN神经元，这种方法使我们能够释放光遗传学的力量来研究心肺控制。